BackgroundEndometrial cancer is the most common gynaecological cancer in high-income countries. In addition to environmental risk factors, genetic predisposition contributes towards endometrial cancer development but is still incompletely defined.MethodsBuilding on genome-wide association studies (GWASs) by the Endometrial Cancer Association Consortium, we conducted a GWAS meta-analysis of 17,278 endometrial cancer cases and 289,180 controls, incorporating biobank samples from the UK, Finland, Estonia and Japan.FindingsGWAS analysis identified five additional risk loci (3p25.2, 3q25.2, 6q22.31, 12q21.2, and 17q24.2). Corresponding gene-based analyses supported findings for three of the five loci, at NAV3 (12q21.2), PPARG (3p25.2), and BPTF (17q24.2), as well as two additional candidate risk regions at ATF7IP2 (16p13.2-p13.13) and RPP21 (6p22.1). Validation genotyping in further independent case-control series replicated the most significant locus at 12q21.2 and corroborated risk variants located intronic to NAV3, the gene for Neuron Navigator 3. Downregulation of NAV3 in endometrial cell lines accelerated cell division and wound healing capacity whereas NAV3 overexpression reduced cell survival and increased cell death, indicating that NAV3 acts as a tumour suppressor in endometrial cells.InterpretationOur large study extends the number of genome-wide significant risk loci identified for endometrial carcinoma by about one-third and proposes a role of NAV3 as a tumour suppressor in this common cancer.FundingThis study was mainly supported by funding from the Wilhelm Sander Foundation, Germany, and the National Health and Medical Research Council (NHMRC) of Australia. A complete list of funding organisations is provided in the acknowledgements.